The protective role of transcription factor Nrf2 in murine macrophage activation syndrome

被引：0

作者：

Gallo, Paul M. ^{[1
]}

Elliott, Em ^{[2
]}

Ford, Grace C. ^{[2
]}

Biswas, Chhanda ^{[2
]}

Wheaton, Jadyn M. ^{[2
]}

Kim, Jihwan ^{[2
]}

Jiang, Connie L. ^{[2
]}

Chu, Niansheng ^{[2
]}

Kreiger, Portia A. ^{[3
]}

Lambert, Michele P. ^{[1
]}

Behrens, Edward M. ^{[2
]}

机构：

[1] Childrens Hosp Philadelphia, Div Hematol, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA

[2] Childrens Hosp Philadelphia, Div Rheumatol, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA

[3] Childrens Hosp Philadelphia, Div Pathol, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA

来源：

JOURNAL OF LEUKOCYTE BIOLOGY | 2025年 / 117卷 / 03期

关键词：

hemophagocytosis; inflammation; macrophage activation syndrome; DISEASE;

D O I：

10.1093/jleuko/qiae225

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Objective: Macrophage activation syndrome (MAS) is characterized by multilineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. Transcription factor Nrf2 is a master regulator of redox homeostasis. In this work, we aim to investigate the role of Nrf2 in murine hyperinflammation and the mechanisms by which Nrf2 activation by red blood cell products regulates proinflammatory cytokine production. Methods: We induced murine MAS in wild-type and Nrf2 knockout (Nrf2-/-) mice by repeat administration of TLR9-agonist CpG. Clinical and biochemical markers of disease were measured including complete blood counts, liver and spleen pathology, serum free heme, ferritin, and cytokine profiles. In vitro bone marrow-derived macrophages and dendritic cells were used to investigate regulation of CpG-induced cytokine expression by oxidized red blood cells and hemin. Results: Patients with hyperinflammatory disease had higher levels of Nrf2 gene expression. Mice with CpG-induced hyperinflammation had elevated systemic lipid peroxidation, which was exacerbated in Nrf2-/- mice. Compared with wild-type control mice, Nrf2-/- mice developed significantly worse organomegaly, organ pathology, and reticulocytosis. Nrf2-/- mice had exacerbated hypercytokinemia in cytokines central MAS physiology: interleukin (IL)-12, interferon gamma, and IL-10. In vitro, we found that oxidized red blood cell lysates and hemin were able to suppress IL-12 transcription and protein production from bone marrow-derived dendritic cells in an Nrf2-dependent manner. Conclusion: Together, our findings show that transcription factor Nrf2 is highly expressed in patients with hyperinflammatory disease and demonstrate a protective role for Nrf2 in a murine model of MAS in part due to Nrf2-mediated suppression of proinflammatory cytokine production.

引用

页数：10

共 22 条

[1]

Behrens EM, 2007, J RHEUMATOL, V34, P1133

[2] Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice [J].

Behrens, Edward M. ;

Canna, Scott W. ;

Slade, Katharine ;

Rao, Sheila ;

Kreiger, Portia A. ;

Paessler, Michele ;

Kambayashi, Taku ;

Koretzky, Gary A. .

JOURNAL OF CLINICAL INVESTIGATION, 2011, 121 (06) :2264-2277

[3] Control of Oxidative Stress and Inflammation in Sickle Cell Disease with the Nrf2 Activator Dimethyl Fumarate [J].

Belcher, John D. ;

Chen, Chunsheng ;

Julia Nguyen ;

Zhang, Ping ;

Abdulla, Fuad ;

Phong Nguyen ;

Killeen, Trevor ;

Xu, Pauline ;

O'Sullivan, Gerry ;

Nath, Karl A. ;

Vercellotti, Gregory M. .

ANTIOXIDANTS & REDOX SIGNALING, 2017, 26 (14) :748-762

[4] Amelioration of Murine Macrophage Activation Syndrome by Monomethyl Fumarate in Both a Heme Oxygenase 1-Dependent and Heme Oxygenase 1-Independent Manner [J].

Biswas, Chhanda ;

Chu, Niansheng ;

Burn, Thomas N. ;

Kreiger, Portia A. ;

Behrens, Edward M. .

ARTHRITIS & RHEUMATOLOGY, 2021, :885-895

[5] Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy [J].

Brachat, Arndt H. ;

Grom, Alexei A. ;

Wulffraat, Nico ;

Brunner, Hermine I. ;

Quartier, Pierre ;

Brik, Riva ;

McCann, Liza ;

Ozdogan, Huri ;

Rutkowska-Sak, Lidia ;

Schneider, Rayfel ;

Gerloni, Valeria ;

Harel, Liora ;

Terreri, Maria ;

Houghton, Kristin ;

Joos, Rik ;

Kingsbury, Daniel ;

Lopez-Benitez, Jorge M. ;

Bek, Stephan ;

Schumacher, Martin ;

Valentin, Marie-Anne ;

Gram, Hermann ;

Abrams, Ken ;

Martini, Alberto ;

Lovell, Daniel J. ;

Nirmala, Nanguneri R. ;

Ruperto, Nicolino .

ARTHRITIS RESEARCH & THERAPY, 2017, 19

[6] Interferon-γ Mediates Anemia but Is Dispensable for Fulminant Toll-like Receptor 9-Induced Macrophage Activation Syndrome and Hemophagocytosis in Mice [J].

Canna, Scott W. ;

Wrobel, Julia ;

Chu, Niansheng ;

Kreiger, Portia A. ;

Paessler, Michele ;

Behrens, Edward M. .

ARTHRITIS AND RHEUMATISM, 2013, 65 (07) :1764-1775

[7] Making Sense of the Cytokine Storm: A Conceptual Framework for Understanding, Diagnosing, and Treating Hemophagocytic Syndromes [J].

Canna, Scott W. ;

Behrens, Edward M. .

PEDIATRIC CLINICS OF NORTH AMERICA, 2012, 59 (02) :329-+

[8] CD163 as a valuable diagnostic and prognostic biomarker of sepsis-associated hemophagocytic lymphohistiocytosis in critically ill children [J].

Cui, Yun ;

Xiong, Xi ;

Ren, Yuqian ;

Wang, Fei ;

Wang, Chunxia ;

Zhang, Yucai .

PEDIATRIC BLOOD & CANCER, 2019, 66 (10)

[9] MotifMap: integrative genome-wide maps of regulatory motif sites for model species [J].

Daily, Kenneth ;

Patel, Vishal R. ;

Rigor, Paul ;

Xie, Xiaohui ;

Baldi, Pierre .

BMC BIOINFORMATICS, 2011, 12

[10]

Green S J, 2001, Curr Protoc Immunol, VChapter 14, DOI 10.1002/0471142735.im1405s12

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